Neuro-cognitive deficits observed in chronic alcoholics often mirror those in individuals with HIV-1-associated dementia (HAD). It has been suggested that alcohol abuse may serve as a co-factor in the development of HAD and exacerbate the symptoms of HIV-1 encephalitis (HIVE). We have previously shown that ethanol affects macrophage function (antigen presentation) and the blood brain barrier (BBS) by enhancing monocyte infiltration via disruption of tight junctions. We further demonstrated that the combined effects of alcohol abuse and HIV-1 infection affect adaptive immune responses and augment neuroinflammation in a small animal model of HIVE. These evidences support the idea that alcohol abuse is an exacerbating factor in HIV-1 central nervous system (CMS) infection through BBB damage and augmented neuroinflammation leading to neuronal injury and diminished anti-viral adaptive immunity. We propose that activation of peroxisome proliferator-activated receptor gamma (PPARgamma, an anti-inflammatory regulatory pathway) diminishes inflammatory cell activation in the CMS, alters their neurotoxic potential and renders protective effects. PPARgamma stimulation in endothelial cells can prevent monocyte transmigration to the brain in the setting of alcohol abuse and HIV-1 infection. In this competing continuation, we will investigate the therapeutic potential of PPARgamma activation and the mechanisms involved in PPARgamma-mediated amelioration of the combined deleterious effects of alcohol abuse by addressing the following questions: 1) Can PPARgamma stimulation alter the neuroprotective/neurotoxic potential of HIV-1-infected, immune activated macrophages [through cytokine and glutamate production, activation of inducible nitric oxide synthase and generation of reactive oxygen species, (ROS)]? 2) Can PPARgamma stimulation attenuate neuroinflammation by decreasing monocyte migration across the BBB (via up-regulation of ROS scavenging enzyme, superoxide dismutase)? And 3) Can PPARgamma agonists diminish neuroinflammation, improve BBB dysfunction and restore impaired immune responses associated with alcohol abuse in an animal model for HIVE? These studies will use cellular models, BBB constructs and an animal model for HIVE to mechanistically address putative protective effects of PPARgamma stimulation on BBB and neurons damaged by alcohol and interactions with HIV-1-infected macrophages. Since the last submission, we obtained additional data (namely significant anti-inflammatory and anti-viral effects of PPARgamma agonists) in support of the hypothesis being tested. The availability of PPARgamma agonists approved for clinical use will permit rapid translation of experimental findings into therapeutic applications.